Itraconazole is a triazole antifungal agent, which has been marketed since 1988. It has broad-spectrum activity against both fungi and bacteria and some protozoa, and is effective against Candida, Aspergillus, Cryptococcus, Histoplasma, and Blastomyces. Itraconazole has strong lipophilicity and is very sparingly soluble in water with a saturated solubility of <1 ng/mL in an aqueous solution at a neutral pH and a saturated solubility of 6 μg/mL in a hydrochloric acid solution at pH=1. Itraconazole is a typical class II drug under the Biopharmaceutics Classification System, and its oral bioavailability depends on the dissolution rate of the drug in the gastrointestinal tract. Because itraconazole is poorly soluble in water, it has a small dissolution rate in the gastrointestinal tract and low oral bioavailability; and also, it is difficult to make an itraconazole injection with a high drug level, resulting in a large dosage amount.
SPORANOX (with itraconazole as a main ingredient) injection, oral liquid and capsule are currently commercially available itraconazole formulations. The solubility of the injection and oral liquid is increased by complexing itraconazole with 2-hydroxypropyl-β-cyclodextrin, but 2-hydroxypropyl-β-cyclodextrin is eliminated primarily by the kidney, so that the elimination time may be prolonged substantially for a patient with serious renal dysfunction, possibly leading to cumulative poisoning. In addition, it has been reported that although the clinical relevance is yet unclear, 2-hydroxypropyl-β-cyclodextrin is found to cause pancreatic cancer in a rat carcinogenicity study of 2-hydroxypropyl-β-cyclodextrin. A study for the SPORANOX capsule has shown that its oral bioavailability highly varies between individuals, and is significantly affected by the gastric acid secretion and diet of patients. Thus, seeking an efficient, low toxic, highly bioavailable, and stable formulation has become a research hotspot in development of itraconazole formulations.
In order to overcome the poor solubility and low bioavailability of itraconazole and the problems of commercial itraconazole formulations, in terms of the formulation, research institutions at home and abroad have made a series of attempts using modern administration techniques, so as to prepare itraconazole into an intravenous emulsion, a self-emulsifying agent and a polymeric micelle, achieving the solubilization effect. However, some problems still exist in the dosage forms. For example, the self-emulsifying agent contains an amount of concentrated hydrochloric acid in the formulation and will lead to damage to the digestive tract for direct administration, and thus further need to be encapsulated in a solid state before oral administration. For the polymeric micelle, polymers used and the safety of respective degraded products in the body have not been reported in literature.
Decreasing the particle size may be used to improve the solubility of a non-water-soluble drug. Supercritical fluid crystallization technique is a new approach for preparing a micro drug, the principle of which is that: a drug solution is mixed with a supercritical fluid such as carbon dioxide under a supercritical state and is sprayed from a spray nozzle so as to form micron-sized particles within several tens of microseconds, where the particle size and crystal form of the drug can be controlled by adjusting the parameters such as pressure, temperature, flow, concentration. The supercritical fluid crystallization technique also enables the drug and polymeric adjuvants to form micron-sized composite particles, so as to ensure the solubility and thus efficacy of the drug, and the composite particles have good crystal stability.